CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy

Store-operated Ca(2+)-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca(2+) upon depletion caused by the opening of intracellular Ca(2+)-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca(2+)-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca(2+)-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca(2+). Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.